Repetitive Head Trauma Induces Chronic Traumatic Encephalopathy by Multiple Mechanisms

Cherry, Jonathan D.; Babcock, Katharine J.; Goldstein, Lee E.

doi:10.1055/s-0040-1713620

Cited by 15 publications

(15 citation statements)

References 91 publications

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“…CTE is a progressive tauopathy found in individuals with a history of repetitive head impacts (RHI) typically obtained through playing contact sports such as American football, hockey, soccer, or rugby, in addition to injuries sustained during military service [5,6]. Evidence from biomechanical computation, helmet sensor data, and neuropathologic autopsy suggests that blood vessels found in the frontal cortex at the depth of the cortical sulcus are observed to be affected the earliest and most severely in CTE, while other regions, including medial and occipital regions such as the calcarine cortex, were relatively spared [6][7][8][9]. The amount of neuroinflammation and severity of pathology has been found to be proportional to the time spent playing contact sports and has been suggested to be an important mechanism of pathogenesis [2,10].…”

Section: Introductionmentioning

confidence: 99%

CCL2 is associated with microglia and macrophage recruitment in chronic traumatic encephalopathy

Cherry

Meng²,

Daley

et al. 2020

J Neuroinflammation

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Background Neuroinflammation has been implicated in the pathogenesis of chronic traumatic encephalopathy (CTE), a progressive neurodegenerative disease association with exposure to repetitive head impacts (RHI) received though playing contact sports such as American football. Past work has implicated early and sustained activation of microglia as a potential driver of tau pathology within the frontal cortex in CTE. However, the RHI induced signals required to recruit microglia to areas of damage and pathology are unknown. Methods Postmortem brain tissue was obtained from 261 individuals across multiple brain banks. Comparisons were made using cases with CTE, cases with Alzheimer’s disease (AD), and cases with no neurodegenerative disease and lacked exposure to RHI (controls). Recruitment of Iba1+ cells around the CTE perivascular lesion was compared to non-lesion vessels. TMEM119 staining was used to characterize microglia or macrophage involvement. The potent chemoattractant CCL2 was analyzed using frozen tissue from the dorsolateral frontal cortex (DLFC) and the calcarine cortex. Finally, the amounts of hyperphosphorylated tau (pTau) and Aβ42 were compared to CCL2 levels to examine possible mechanistic pathways. Results An increase in Iba1+ cells was found around blood vessels with perivascular tau pathology compared to non-affected vessels in individuals with RHI. TMEM119 staining revealed the majority of the Iba1+ cells were microglia. CCL2 protein levels in the DLFC were found to correlate with greater years of playing American football, the density of Iba1+ cells, the density of CD68+ cells, and increased CTE severity. When comparing across multiple brain regions, CCL2 increases were more pronounced in the DLFC than the calcarine cortex in cases with RHI but not in AD. When examining the individual contribution of pathogenic proteins to CCL2 changes, pTau correlated with CCL2, independent of age at death and Aβ42 in AD and CTE. Although levels of Aβ42 were not correlated with CCL2 in cases with CTE, in males in the AD group, Aβ42 trended toward an inverse relationship with CCL2 suggesting possible gender associations. Conclusion Overall, CCL2 is implicated in the pathways recruiting microglia and the development of pTau pathology after exposure to RHI, and may represent a future therapeutic target in CTE.

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Section: Introductionmentioning

confidence: 99%

CCL2 is associated with microglia and macrophage recruitment in chronic traumatic encephalopathy

Cherry

Meng²,

Daley

et al. 2020

J Neuroinflammation

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“…Pathologies such as vascular dysfunction, axonal damage and neuroinflammation occur acutely after head injury and persist, implicating them as possible initiating mechanisms of CTE. The spatial distribution of these pathologies is particularly relevant as the forces caused by head impact are concentrated in regions of structural inhomogeneity such as the sulcal depth and the vessel-tissue boundary [ 22 ]. Anatomical studies of non-aggregate pathologies are therefore key to understanding the disease process in CTE.…”

Section: Discussionmentioning

confidence: 99%

“…Astrogliosis could contribute to progression from acute head injury to chronic degeneration as astrocyte endfeet are a component of the neurovascular unit and play an essential role in regulating glymphatic clearance of proteins like p-tau and beta-amyloid through the expression of the water channel aquaporin IV. However, when astrocytes become reactive, the perivascular presence of aquaporin IV is lost, which can lead to impaired glymphatic clearance and accumulation of p-tau and beta-amyloid [ 22 , 45 ]. Therefore, future histology studies investigating the spatial relationship between markers of astrogliosis, aggregated protein pathologies and vasculature would be valuable.…”

Section: Discussionmentioning

confidence: 99%

Neuropathology in chronic traumatic encephalopathy: a systematic review of comparative post-mortem histology literature

Murray

Osterman

Bell

et al. 2022

acta neuropathol commun

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Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with repetitive head trauma and is characterised by the perivascular accumulation of hyperphosphorylated tau (p-tau) in the depths of cortical sulci. CTE can only be diagnosed postmortem and the cellular mechanisms of disease causation remain to be elucidated. Understanding the full scope of the pathological changes currently identified in CTE is necessary to identify areas requiring further research. This systematic review summarises the current literature on CTE pathology from postmortem human tissue histology studies published until 31 December 2021. Publications were included if they quantitively or qualitatively compared postmortem human tissue pathology in CTE to neuropathologically normal cases or other neurodegenerative diseases such as Alzheimer’s disease (AD). Pathological entities investigated included p-tau, beta-amyloid, TDP-43, Lewy bodies, astrogliosis, microgliosis, axonopathy, vascular dysfunction, and cell stress. Of these pathologies, p-tau was the most frequently investigated, with limited reports on other pathological features such as vascular dysfunction, astrogliosis, and microgliosis. Consistent increases in p-tau, TDP-43, microgliosis, axonopathy, and cell stress were reported in CTE cases compared to neuropathologically normal cases. However, there was no clear consensus on how these pathologies compared to AD. The CTE cases used for these studies were predominantly from the VA-BU-CLF brain bank, with American football and boxing as the most frequent sources of repetitive head injury exposure. Overall, this systematic review highlights gaps in the literature and proposes three priorities for future research including: 1. The need for studies of CTE cases with more diverse head injury exposure profiles to understand the consistency of pathology changes between different populations. 2. The need for more studies that compare CTE with normal ageing and AD to further clarify the pathological signature of CTE for diagnostic purposes and to understand the disease process. 3. Further research on non-aggregate pathologies in CTE, such as vascular dysfunction and neuroinflammation. These are some of the least investigated features of CTE pathology despite being implicated in the acute phase response following traumatic head injury.

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“…15 Many studies show a significant association between cumulative exposure to repetitive head trauma, judged by the length of the sportive career, and the risk for severity of CTE. 16 There is also a significant relationship with the length of the sport activities and the age of death. 17 TBI significantly increases the risk of developing AD and Parkinson's disease.…”

Section: Clinical Featuresmentioning

confidence: 99%

Chronic traumatic encephalopathy: an update review

Reuck¹

2021

JNSK

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Chronic traumatic encephalopathy is a progressive neurodegenerative disease occurring in retired sportspersons who have received several head blows with concussions during their games. The clinical symptoms start with mood disorders and with a progressive evolution into dementia and Parkinsonism. The disease is due to a progressive accumulation of hyperphosphorilated tau in neurons as neurofibrillary tangles, abnormal neurites and inclusions in astrocytes around small vessels. There is a tendency of the lesions to occur in clusters at the sulcal depths of the cerebral cortex. Chronic traumatic encephalopathy has to be differentiated from Alzheimer’s disease, in which head trauma can also increase the illness symptoms. Recently, new tracers in positron emission topography of the brain have been used for a better evaluation of chronic traumatic encephalopathy. There is actually no treatment that allows to cure or to slowdown the evolution of chronic traumatic encephalopathy. However, new treatment studies are recently conducted and in progress.

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Repetitive Head Trauma Induces Chronic Traumatic Encephalopathy by Multiple Mechanisms

Cited by 15 publications

References 91 publications

CCL2 is associated with microglia and macrophage recruitment in chronic traumatic encephalopathy

CCL2 is associated with microglia and macrophage recruitment in chronic traumatic encephalopathy

Neuropathology in chronic traumatic encephalopathy: a systematic review of comparative post-mortem histology literature

Chronic traumatic encephalopathy: an update review

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